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PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons

Konstantinos Toskas, Behzad Yaghmaeian-Salmani, Olga Skiteva, Wojciech Paslawski, Linda Gillberg, Vasiliki Skara, Irene Antoniou, Erik Södersten, Per Svenningsson, Karima Chergui, Markus Ringnér, Thomas Perlmann, Johan Holmberg
doi: https://doi.org/10.1101/2022.01.24.477226
Konstantinos Toskas
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Behzad Yaghmaeian-Salmani
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Olga Skiteva
2Department of Physiology and Pharmacology, Karolinska Institutet, BioClinicum J5:20 Neuro, Visionsgatan 4, 171 64 Solna, Sweden
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Wojciech Paslawski
3Department of Clinical Neuroscience, Karolinska Institutet, SE-17165, Stockholm, Sweden
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Linda Gillberg
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Vasiliki Skara
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Irene Antoniou
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Erik Södersten
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Per Svenningsson
3Department of Clinical Neuroscience, Karolinska Institutet, SE-17165, Stockholm, Sweden
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Karima Chergui
2Department of Physiology and Pharmacology, Karolinska Institutet, BioClinicum J5:20 Neuro, Visionsgatan 4, 171 64 Solna, Sweden
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Markus Ringnér
4Department of Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University, Sölvegatan 35, SE-223 62 Lund, Sweden
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Thomas Perlmann
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
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Johan Holmberg
1Department of Cell and Molecular Biology, Karolinska Institutet, Solnavägen 9, SE-171 65 Stockholm, Sweden
5Department of Molecular Biology, Umeå University, SE-901 87, Umeå, Sweden
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  • For correspondence: johan.holmberg@ki.se
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Abstract

How neurons in the CNS can maintain cellular identity over an entire lifespan remains largely unknown. Here we show that long-term maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2-component, Eed, in these neurons, resulted in global loss of H3K27me3, followed by a gradual activation of genes harbouring both H3K27me3 and H3K9me3 modifications. Notably, H3K9me3 was also lost at these PRC2-targets prior to gene activation. Neuronal survival was not compromised, instead there was a reduction in subtype specific gene expression as well as a progressive impairment of dopaminergic or serotonergic neuronal function leading to behavioural deficits characteristic of Parkinson’s disease (PD) or mood disorders, respectively. Single cell analysis revealed an unexpected subtype specific vulnerability to loss of PRC2-repression in dopamine neurons of the substantia nigra, the neurons primarily affected in PD. Taken together, our study reveals that a PRC2-dependent non-permissive chromatin state is essential to maintain subtype identity and function of dopaminergic and serotonergic neurons.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 24, 2022.
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PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons
Konstantinos Toskas, Behzad Yaghmaeian-Salmani, Olga Skiteva, Wojciech Paslawski, Linda Gillberg, Vasiliki Skara, Irene Antoniou, Erik Södersten, Per Svenningsson, Karima Chergui, Markus Ringnér, Thomas Perlmann, Johan Holmberg
bioRxiv 2022.01.24.477226; doi: https://doi.org/10.1101/2022.01.24.477226
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PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons
Konstantinos Toskas, Behzad Yaghmaeian-Salmani, Olga Skiteva, Wojciech Paslawski, Linda Gillberg, Vasiliki Skara, Irene Antoniou, Erik Södersten, Per Svenningsson, Karima Chergui, Markus Ringnér, Thomas Perlmann, Johan Holmberg
bioRxiv 2022.01.24.477226; doi: https://doi.org/10.1101/2022.01.24.477226

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